Alternative Binding Modes Identified for Growth and Differentiation Factor-associated Serum Protein (GASP) Family Antagonism of Myostatin
Abstract
Myostatin, a member of the TGF-β family of ligands, is a strong negative regulator of muscle growth. As such, it is a prime therapeutic target for muscle wasting disorders. Similar to other TGF-β family ligands, myostatin is neutralized by binding one of a number of structurally diverse antagonists. Included are the antagonists GASP-1 and GASP-2, which are unique in that they specifically antagonize myostatin. However, little is known from a structural standpoint describing the interactions of GASP antagonists with myostatin. In this paper, we present the First low resolution solution structure of myostatin-free and myostatin-bound states of GASP-1 and GASP-2. Our studies have revealed GASP-1, which is 100 times more potent than GASP-2, preferentially binds myostatin in an asymmetrical 1:1 complex, whereas GASP-2 binds in a symmetrical 2:1 complex. Additionally, C-terminal truncations of GASP-1 result in less potent myostatin inhibitors that form a 2:1 complex, suggesting that the C-terminal domains of GASP-1 are the primary mediators for asymmetric complex formation. Overall, this study provides a new perspective on TGF-β antagonism, where closely related antagonists can utilize different ligand-binding strategies.
- Authors:
-
- Univ. of Cincinnati, OH (United States)
- Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES); American Heart Association (AHA); Muscular Dystrophy Association (MDA)
- OSTI Identifier:
- 1236259
- Grant/Contract Number:
- R01AR060636; R01GM105404; 12PRE11790027; 240087
- Resource Type:
- Journal Article: Accepted Manuscript
- Journal Name:
- Journal of Biological Chemistry
- Additional Journal Information:
- Journal Volume: 290; Journal Issue: 12; Journal ID: ISSN 0021-9258
- Publisher:
- American Society for Biochemistry and Molecular Biology
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; Analytical Ultracentrifugation; Myostatin; Small Angle X-ray Scattering (SAXS); Structural Biology; Transforming Growth Factor Beta (TGF-B); Growth and Differentiation-associated Serum Protein; Growth and Differentiation factor-8 (GDF-8); WFIKKN
Citation Formats
Walker, Ryan G., Angerman, Elizabeth B., Kattamuri, Chandramohan, Lee, Yun-Sil, Lee, Se-Jin, and Thompson, Thomas B. Alternative Binding Modes Identified for Growth and Differentiation Factor-associated Serum Protein (GASP) Family Antagonism of Myostatin. United States: N. p., 2015.
Web. doi:10.1074/jbc.m114.624130.
Walker, Ryan G., Angerman, Elizabeth B., Kattamuri, Chandramohan, Lee, Yun-Sil, Lee, Se-Jin, & Thompson, Thomas B. Alternative Binding Modes Identified for Growth and Differentiation Factor-associated Serum Protein (GASP) Family Antagonism of Myostatin. United States. https://doi.org/10.1074/jbc.m114.624130
Walker, Ryan G., Angerman, Elizabeth B., Kattamuri, Chandramohan, Lee, Yun-Sil, Lee, Se-Jin, and Thompson, Thomas B. 2015.
"Alternative Binding Modes Identified for Growth and Differentiation Factor-associated Serum Protein (GASP) Family Antagonism of Myostatin". United States. https://doi.org/10.1074/jbc.m114.624130. https://www.osti.gov/servlets/purl/1236259.
@article{osti_1236259,
title = {Alternative Binding Modes Identified for Growth and Differentiation Factor-associated Serum Protein (GASP) Family Antagonism of Myostatin},
author = {Walker, Ryan G. and Angerman, Elizabeth B. and Kattamuri, Chandramohan and Lee, Yun-Sil and Lee, Se-Jin and Thompson, Thomas B.},
abstractNote = {Myostatin, a member of the TGF-β family of ligands, is a strong negative regulator of muscle growth. As such, it is a prime therapeutic target for muscle wasting disorders. Similar to other TGF-β family ligands, myostatin is neutralized by binding one of a number of structurally diverse antagonists. Included are the antagonists GASP-1 and GASP-2, which are unique in that they specifically antagonize myostatin. However, little is known from a structural standpoint describing the interactions of GASP antagonists with myostatin. In this paper, we present the First low resolution solution structure of myostatin-free and myostatin-bound states of GASP-1 and GASP-2. Our studies have revealed GASP-1, which is 100 times more potent than GASP-2, preferentially binds myostatin in an asymmetrical 1:1 complex, whereas GASP-2 binds in a symmetrical 2:1 complex. Additionally, C-terminal truncations of GASP-1 result in less potent myostatin inhibitors that form a 2:1 complex, suggesting that the C-terminal domains of GASP-1 are the primary mediators for asymmetric complex formation. Overall, this study provides a new perspective on TGF-β antagonism, where closely related antagonists can utilize different ligand-binding strategies.},
doi = {10.1074/jbc.m114.624130},
url = {https://www.osti.gov/biblio/1236259},
journal = {Journal of Biological Chemistry},
issn = {0021-9258},
number = 12,
volume = 290,
place = {United States},
year = {Thu Feb 05 00:00:00 EST 2015},
month = {Thu Feb 05 00:00:00 EST 2015}
}
Web of Science
Works referenced in this record:
Macromolecular Size-and-Shape Distributions by Sedimentation Velocity Analytical Ultracentrifugation
journal, June 2006
- Brown, Patrick H.; Schuck, Peter
- Biophysical Journal, Vol. 90, Issue 12
Uniqueness of ab initio shape determination in small-angle scattering
journal, April 2003
- Volkov, Vladimir V.; Svergun, Dmitri I.
- Journal of Applied Crystallography, Vol. 36, Issue 3, p. 860-864
WFIKKN1 and WFIKKN2 bind growth factors TGFβ1, BMP2 and BMP4 but do not inhibit their signalling activity: WFIKKNs bind several members of the TGFβ family
journal, November 2010
- Szláma, György; Kondás, Katalin; Trexler, Mária
- FEBS Journal, Vol. 277, Issue 24
DAMMIF, a program for rapid ab-initio shape determination in small-angle scattering
journal, January 2009
- Franke, Daniel; Svergun, Dmitri I.
- Journal of Applied Crystallography, Vol. 42, Issue 2, p. 342-346
High-Throughput SAXS for the Characterization of Biomolecules in Solution: A Practical Approach
book, October 2013
- Dyer, Kevin N.; Hammel, Michal; Rambo, Robert P.
- Structural Genomics
The structure of myostatin:follistatin 288: insights into receptor utilization and heparin binding
journal, July 2009
- Cash, Jennifer N.; Rejon, Carlis A.; McPherron, Alexandra C.
- The EMBO Journal, Vol. 28, Issue 17
Extracellular Regulation of Myostatin: A Molecular Rheostat for Muscle Mass
journal, December 2010
- Lee, Se-Jin
- Immunology‚ Endocrine & Metabolic Agents in Medicinal Chemistry, Vol. 10, Issue 4
Development of a Small-Molecule Screening Method for Inhibitors of Cellular Response to Myostatin and Activin A
journal, August 2013
- Cash, Jennifer N.; Angerman, Elizabeth B.; Kirby, R. Jason
- Journal of Biomolecular Screening, Vol. 18, Issue 7
Double muscling in cattle due to mutations in the myostatin gene
journal, November 1997
- McPherron, A. C.; Lee, S. -J.
- Proceedings of the National Academy of Sciences, Vol. 94, Issue 23
Regulation of Myostatin in Vivo by Growth and Differentiation Factor-Associated Serum Protein-1: A Novel Protein with Protease Inhibitor and Follistatin Domains
journal, June 2003
- Hill, Jennifer J.; Qiu, Yongchang; Hewick, Rodney M.
- Molecular Endocrinology, Vol. 17, Issue 6
Follistatin complexes Myostatin and antagonises Myostatin-mediated inhibition of myogenesis
journal, June 2004
- Amthor, Helge; Nicholas, Gina; McKinnell, Iain
- Developmental Biology, Vol. 270, Issue 1
Nanoscale structure of the BMP antagonist chordin supports cooperative BMP binding
journal, August 2014
- Troilo, H.; Zuk, A. V.; Tunnicliffe, R. B.
- Proceedings of the National Academy of Sciences, Vol. 111, Issue 36
Combined Affinity and Rate Constant Distributions of Ligand Populations from Experimental Surface Binding Kinetics and Equilibria
journal, June 2003
- Svitel, Juraj; Balbo, Andrea; Mariuzza, Roy A.
- Biophysical Journal, Vol. 84, Issue 6
Regulation of myostatin activity and muscle growth
journal, July 2001
- Lee, S. -J.; McPherron, A. C.
- Proceedings of the National Academy of Sciences, Vol. 98, Issue 16
GASP/WFIKKN Proteins: Evolutionary Aspects of Their Functions
journal, August 2012
- Monestier, Olivier; Brun, Caroline; Cocquempot, Olivier
- PLoS ONE, Vol. 7, Issue 8
Gdf-8 Propeptide Binds to GDF-8 and Antagonizes Biological Activity by Inhibiting GDF-8 Receptor Binding
journal, January 2001
- Tries, R. Scott; Chen, Tom; Da Vies, Monique V.
- Growth Factors, Vol. 18, Issue 4
Characterization of Follistatin-Type Domains and Their Contribution to Myostatin and Activin A Antagonism
journal, July 2012
- Cash, Jennifer N.; Angerman, Elizabeth B.; Keutmann, Henry T.
- Molecular Endocrinology, Vol. 26, Issue 7
Regulation of anterior/posterior patterning of the axial skeleton by growth/differentiation factor 11
journal, July 1999
- McPherron, Alexandra C.; Lawler, Ann M.; Lee, Se-Jin
- Nature Genetics, Vol. 22, Issue 3
Transgenic expression of a myostatin inhibitor derived from follistatin increases skeletal muscle mass and ameliorates dystrophic pathology in mdx mice
journal, September 2007
- Nakatani, Masashi; Takehara, Yuka; Sugino, Hiromu
- The FASEB Journal, Vol. 22, Issue 2
Murine GASP-1 N -Glycosylation is not Essential for its Activity on C2C12 Myogenic Cells but Alters its Secretion
journal, January 2012
- Brun, Caroline; Monestier, Olivier; Legardinier, Sébastien
- Cellular Physiology and Biochemistry, Vol. 30, Issue 3
A human protein containing multiple types of protease-inhibitory modules
journal, March 2001
- Trexler, M.; Banyai, L.; Patthy, L.
- Proceedings of the National Academy of Sciences, Vol. 98, Issue 7
The Myostatin Propeptide and the Follistatin-related Gene Are Inhibitory Binding Proteins of Myostatin in Normal Serum
journal, August 2002
- Hill, Jennifer J.; Davies, Monique V.; Pearson, Adele A.
- Journal of Biological Chemistry, Vol. 277, Issue 43
Improved muscle healing through enhanced regeneration and reduced fibrosis in myostatin-null mice
journal, August 2005
- McCroskery, S.
- Journal of Cell Science, Vol. 118, Issue 15
Characterizing flexible and intrinsically unstructured biological macromolecules by SAS using the Porod-Debye law
journal, April 2011
- Rambo, Robert P.; Tainer, John A.
- Biopolymers, Vol. 95, Issue 8
Size-Distribution Analysis of Macromolecules by Sedimentation Velocity Ultracentrifugation and Lamm Equation Modeling
journal, March 2000
- Schuck, Peter
- Biophysical Journal, Vol. 78, Issue 3
Crystal Structure Analysis Reveals How the Chordin Family Member Crossveinless 2 Blocks BMP-2 Receptor Binding
journal, May 2008
- Zhang, Jin-li; Qiu, Li-yan; Kotzsch, Alexander
- Developmental Cell, Vol. 14, Issue 5
Structure of Myostatin·Follistatin-like 3: N-TERMINAL DOMAINS OF FOLLISTATIN-TYPE MOLECULES EXHIBIT ALTERNATE MODES OF BINDING
journal, November 2011
- Cash, Jennifer N.; Angerman, Elizabeth B.; Kattamuri, Chandramohan
- Journal of Biological Chemistry, Vol. 287, Issue 2
Latent myostatin has significant activity and this activity is controlled more efficiently by WFIKKN 1 than by WFIKKN 2
journal, July 2013
- Szláma, György; Trexler, Mária; Patthy, László
- The FEBS Journal, Vol. 280, Issue 16
von Willebrand Factor Type C Domain-containing Proteins Regulate Bone Morphogenetic Protein Signaling through Different Recognition Mechanisms
journal, May 2007
- Zhang, Jin-Li; Huang, Yi; Qiu, Li-Yan
- Journal of Biological Chemistry, Vol. 282, Issue 27
Biological Activity of Follistatin Isoforms and Follistatin-Like-3 Is Dependent on Differential Cell Surface Binding and Specificity for Activin, Myostatin, and Bone Morphogenetic Proteins
journal, July 2006
- Sidis, Yisrael; Mukherjee, Abir; Keutmann, Henry
- Endocrinology, Vol. 147, Issue 7
Regulation of GDF-11 and myostatin activity by GASP-1 and GASP-2
journal, September 2013
- Lee, Y. -S.; Lee, S. -J.
- Proceedings of the National Academy of Sciences, Vol. 110, Issue 39
Muscle regeneration in the prolonged absence of myostatin
journal, February 2005
- Wagner, K. R.; Liu, X.; Chang, X.
- Proceedings of the National Academy of Sciences, Vol. 102, Issue 7
The Structure of the Follistatin:Activin Complex Reveals Antagonism of Both Type I and Type II Receptor Binding
journal, October 2005
- Thompson, Thomas B.; Lerch, Thomas F.; Cook, Robert W.
- Developmental Cell, Vol. 9, Issue 4
Direct binding of follistatin to a complex of bone-morphogenetic protein and its receptor inhibits ventral and epidermal cell fates in early Xenopus embryo
journal, August 1998
- Iemura, Shun-ichiro; Yamamoto, Takamasa S.; Takagi, Chiyo
- Proceedings of the National Academy of Sciences, Vol. 95, Issue 16
The Structure of FSTL3·Activin A Complex
journal, September 2008
- Stamler, Robin; Keutmann, Henry T.; Sidis, Yisrael
- Journal of Biological Chemistry, Vol. 283, Issue 47
Regulation of skeletal muscle mass in mice by a new TGF-p superfamily member
journal, May 1997
- McPherron, Alexandra C.; Lawler, Ann M.; Lee, Se-Jin
- Nature, Vol. 387, Issue 6628
Structural basis of BMP signalling inhibition by the cystine knot protein Noggin
journal, December 2002
- Groppe, Jay; Greenwald, Jason; Wiater, Ezra
- Nature, Vol. 420, Issue 6916
Works referencing / citing this record:
Variation in zygotic CRISPR/Cas9 gene editing outcomes generates novel reporter and deletion alleles at the Gdf11 locus
journal, December 2019
- Goldstein, Jill M.; Valido, Austin; Lewandowski, Jordan P.
- Scientific Reports, Vol. 9, Issue 1
Molecular characterization of latent GDF8 reveals mechanisms of activation
journal, January 2018
- Walker, Ryan G.; McCoy, Jason C.; Czepnik, Magdalena
- Proceedings of the National Academy of Sciences, Vol. 115, Issue 5
Crystal structure of the WFIKKN2 follistatin domain reveals insight into how it inhibits growth differentiation factor 8 (GDF8) and GDF11
journal, April 2019
- McCoy, Jason C.; Walker, Ryan G.; Murray, Nathan H.
- Journal of Biological Chemistry, Vol. 294, Issue 16
GASP‐2 overexpressing mice exhibit a hypermuscular phenotype with contrasting molecular effects compared to GASP‐1 transgenics
journal, January 2020
- Parenté, Alexis; Boukredine, Axel; Baraige, Fabienne
- The FASEB Journal, Vol. 34, Issue 3
Biochemistry and Biology of GDF11 and Myostatin: Similarities, Differences, and Questions for Future Investigation
journal, April 2016
- Walker, Ryan G.; Poggioli, Tommaso; Katsimpardi, Lida
- Circulation Research, Vol. 118, Issue 7
Structural biology of the TGFβ family
journal, October 2019
- Goebel, Erich J.; Hart, Kaitlin N.; McCoy, Jason C.
- Experimental Biology and Medicine, Vol. 244, Issue 17
Structural basis for potency differences between GDF8 and GDF11
journal, March 2017
- Walker, Ryan G.; Czepnik, Magdalena; Goebel, Erich J.
- BMC Biology, Vol. 15, Issue 1
Structure of the human myostatin precursor and determinants of growth factor latency
journal, December 2017
- Cotton, Thomas R.; Fischer, Gerhard; Wang, Xuelu
- The EMBO Journal, Vol. 37, Issue 3
Structure of the human myostatin precursor and determinants of growth factor latency.
text, January 2018
- Cotton, Thomas R.; Fischer, Gerhard; Wang, Xuelu
- Apollo - University of Cambridge Repository
Structural basis for potency differences between GDF8 and GDF11.
journalarticle, January 2017
- Walker, Ryan G.; Czepnik, Magdalena; Goebel, Erich J.
- Springer Science and Business Media LLC
Enhancement of C2C12 myoblast proliferation and differentiation by GASP-2, a myostatin inhibitor
journal, July 2016
- Pèrié, Luce; Parenté, Alexis; Brun, Caroline
- Biochemistry and Biophysics Reports, Vol. 6
Correction to Binding Properties of the Transforming Growth Factor-β Coreceptor Betaglycan: Proposed Mechanism for Potentiation of Receptor Complex Assembly and Signaling
journal, July 2017
- Villarreal, Maria M.; Kim, Sun Kyung; Barron, Lindsey
- Biochemistry, Vol. 56, Issue 28
Variation in zygotic CRISPR/Cas9 gene editing outcomes generates novel reporter and deletion alleles at the Gdf11 locus
journal, December 2019
- Goldstein, Jill M.; Valido, Austin; Lewandowski, Jordan P.
- Scientific Reports, Vol. 9, Issue 1
Molecular characterization of latent GDF8 reveals mechanisms of activation
journal, January 2018
- Walker, Ryan G.; McCoy, Jason C.; Czepnik, Magdalena
- Proceedings of the National Academy of Sciences, Vol. 115, Issue 5
Structural basis for potency differences between GDF8 and GDF11
journal, March 2017
- Walker, Ryan G.; Czepnik, Magdalena; Goebel, Erich J.
- BMC Biology, Vol. 15, Issue 1
Beyond the Big Five: Investigating Myostatin Structure, Polymorphism and Expression in Camelus dromedarius
journal, June 2019
- Favia, Maria; Fitak, Robert; Guerra, Lorenzo
- Frontiers in Genetics, Vol. 10